dienol ether double cyclization reactions

Tetrahedron Letters 56 (2015) 3105–3107

Contents lists available at ScienceDirect

Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet

Stereocontrolled intramolecular iron-mediated tandem [6+2]-ene-type diene/dienol ether double cyclization reactions Anthony J. Pearson ⇑, Sheng Zhang Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, United States

a r t i c l e

i n f o

Article history: Received 6 November 2014 Accepted 28 November 2014 Available online 5 December 2014 Keywords: Tricarbonyliron Diene Cycloisomerization Ene reaction

a b s t r a c t A stereocontrolled intramolecular iron-mediated diene/diene tandem double cyclocoupling reaction has been explored using vinyl ethers as the olefin partners. Diastereomerically pure spirotricyclic products with functionalized (alkoxymethyl) side chains can be formed efficiently under photothermal conditions. With a methoxy substituent on the iron-complexed cyclohexadiene core, demetallation and acidic hydrolysis of the cyclocoupling product afforded a cyclohexenone ring. Ó 2014 Elsevier Ltd. All rights reserved.

Introduction Iron carbonyl complexes of alkenes and dienes, as well as their derived allylic and dienyl systems, have found numerous applications as stoichiometric intermediates in organic synthesis, mostly utilizing the ability of the tricarbonyliron group to stabilize otherwise highly reactive species, to act as a stereodirecting moiety, and to act as a protecting group for 1,3-dienes.1 Our group has developed a promising stereocontrolled intramolecular iron-mediated diene/olefin cyclocoupling procedure, equivalent to a [6+2] ene-type reaction, which generates spirolactams,2 spirolactones,2 spirothiolactones,3 and spiroalkane derivatives4 under thermal or photothermal conditions (Eq. 1). Based on this reaction, a double cyclization process, resulting from two consecutive [6+2] ene-type reactions, was also developed in our laboratory (Eq. 2).5 The overall reaction manifold takes advantage of the ability of a tricarbonyliron group to protect the attached cyclohexadiene moiety and prevent intramolecular Diels–Alder reactions, thus directing the substrate along a normally inaccessible ene reaction pathway. The work described in this report aims to examine the tandem double cyclization using an electron rich 2p component in the second ene reaction, thereby further expanding the scope of the cyclocoupling to include dienol ethers, which would result in tricyclic molecules having (protected) hydroxymethyl side chains (R0 = alkoxy in Eq. 2).6

⇑ Corresponding author. E-mail address: [email protected] (A.J. Pearson). http://dx.doi.org/10.1016/j.tetlet.2014.11.129 0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

Fe(CO)3

Bu2O, CO, 142 ºC or benzene, CO, 350 nm, reflux

Fe(CO)3 Me

ð1Þ

X X = NPh, O, S, CH2 O

O

1

R

X 2

Fe(CO)3

R'

NPh

(OC)3Fe Bu2O, 142 ºC

H

1 atm. CO

R = H or OMe; R' = H or CO2Me

CH2R'

H O

O 3

R

ð2Þ

N Ph 4

Results and discussion Known carboxylic acids 5a7 and 5b8 were each coupled via their acyl mesylates with amine 6 to afford amides 7a and 7b (Scheme 1). Deprotection of 7a and 7b by treatment with an 8:1:1 mixture of MeOH/H2O/HCl afforded alcohols 8a and 8b, which were oxidized using the Mukaiyama protocol9 to afford aldehydes 9a and 9b without loss of the Fe(CO)3 moiety. Complexes 9a and 9b were each reacted with (methoxymethyl)triphenylphosphorane to afford methoxy dienyl ethers 10a (E/Z = 0.9:1) and 10b (E/Z = 1.5:1). We also planned to study cyclizations of the corresponding benzyl ethers, because a benzyl protecting group is easier to remove from the anticipated cyclization products when required. Accordingly, 9a and 9b were each treated with

3106

A.J. Pearson, S. Zhang / Tetrahedron Letters 56 (2015) 3105–3107

R

Fe(CO)3

COOH

R

Fe(CO)3

DIPEA, MsCl, 0 ºC;

R

OMEM HCl, MeOH

NPh

NPh

PhHN

OH

Fe(CO)3

OMEM 6

5a R = H 5b R = OMe

O

O

8a R = H (81%) 8b R = OMe (92%)

7a R = H (88%) 7b R = OMe (93%) R

Fe(CO)3

R

O

MgBr

Fe(CO)3

OR'

Ph3P=CHOR'

H

NPh

NPh ADDP

O

O

10a R = H, R' = Me (77%) 10b R = OMe, R' = Me (91%) 10c R = H, R' = Bn (77%) 10d R = OMe, R' = Bn (77%)

9a R = H (77%) 9b R = OMe (78%) Scheme 1.

(benzyloxymethyl)triphenylphosphorane to give benzyloxydienyl derivatives 10c (E/Z = 1.3:1) and 10d (E/Z = 1.2:1). In order to assess the potential for the pendant dienol ethers to engage in our tandem [6+2] ene-type cyclocoupling reaction, we first examined thermal conditions that were successful with complexes 3 (Eq. 2). Accordingly, 10a was heated in n-Bu2O (0.02 mmol/mL) under CO atmosphere at 142 °C for 16 h, which afforded a separable mixture of the anticipated product 11a and a side product 12 that results from an iron-mediated [4+4] cycloaddition product (Eq. 3, 2:1 in favor of 11a from the 1H NMR spectrum of the crude product). This type of reaction has been previously observed as the major pathway when complexes related to 3 were treated with a controlled amount of trimethylamine-N-oxide to effect loss of a carbonyl ligand from the iron complex,10 but we have not previously observed the formation of [4+4] adducts under standard thermal reaction conditions. A similar treatment of complex 10a with Me3NO was unproductive. Presumably the electron rich nature of the dienol ether side chain plays a role in the outcome of this reaction. Cyclization of 10a under photothermal conditions, however, afforded the double-ene cyclization product 11a together with the demetallated diene 13a as the major components (see Table 1). The mixture was treated directly with Me3NO to afford 13a as the major product in 70% isolated yield, together with a minor amount of 12 (7%). R'O

H CH2OR'

(OC)3Fe Bu2O, 142 ºC

+

10a or 10c 1 atm. CO

H O

N Ph

11a R' = Me 11c R' = Bn

O

N Ph

12 R' = Me 14 R' = Bn

ð3Þ We were interested in determining whether the nature of the ether group on the pendant diene affects the partitioning between ene- and [4+4]-cyclization pathways. Accordingly 10c, which has a somewhat more sterically demanding ether group on the side chain, was reacted under purely thermal conditions and gave a mixture of the anticipated product 11c and the [4+4] cycloaddition product 14 in 2.8:1 ratio, as well as some unidentifiable side products. Reaction of 10c under photothermal conditions, in contrast, gave an 11:1 NMR ratio of double cyclization products (11c and its demetallated form 13c—see Table 1) over compound 14. The crude mixture was then stirred with Me3NO in benzene, affording 13c in 68% overall yield from 10c. The results indicate that the nature of the O-alkyl substituent has only marginal effect on the outcome of the reaction, and this was not pursued any further.

Table 1 Photothermal cyclization of complexes 10

Me3NO benzene Benzene, CO, 350 nm, reflux

(OC)3Fe

R

R

H CH2OR' +

10

H O

H O

N Ph

N Ph 13

11

a

H CH2OR'

Reactant

R, R0

Product

Yield 13a

10a 10b 10c 10d

H, Me OMe, Me H, Bn OMe, Bn

13a 13b 13c 13d

70 72 68 68

Overall yield from 10 after demetallation, two steps.

We have previously employed a methoxy substituent at C-3 on the cyclohexadienylcarboxamide–Fe(CO)3 complexes to control the stereochemical outcome of single ene-type cyclizations as well as to generate useful cyclohexenone functionality in the products that result from both single- and tandem double ene-type reactions.8 To assess the outcome of using this moiety in the present reactions, complexes 10b and 10d were cyclized under thermal conditions, but each gave a complex mixture containing less than 20% of the desired product (by NMR spectroscopy). Reaction of 10b or 10d under photothermal conditions, however, gave almost exclusive conversion to the double cyclization products 13b and 13d after direct demetallation using excess Me3NO; no [4+4] adducts were detected in the crude product mixtures from these reactions, the mass balance for the cyclization process being accounted for as unreacted and/or demetallated starting material. Dienes 13b and 13d were then each hydrolyzed using oxalic acid, affording a,b-unsaturated ketones 15a and 15b, respectively (Eq. 4). OMe CH OR' 2 H H O

N Ph

13b R' = Me 13d R' = Bn

O Oxalic acid

H CH2OR'

H

H2O, MeOH O

N Ph

15a R' = Me (75%) 15b R' = Bn (72%)

ð4Þ

A.J. Pearson, S. Zhang / Tetrahedron Letters 56 (2015) 3105–3107

3107

Conclusions

References and notes

In conclusion, we have shown that a tandem double [6+2] ene-type cyclization, that is mediated by an iron carbonyl moiety attached to a cyclohexa-1,3-diene, can be performed using a dienol ether as the pendant diene, resulting in a spirotricyclic molecule that has alkoxymethyl functionality at the cyclization terminus. Competing [4+4] cycloaddition that occurs during the thermally activated reaction can be ameliorated by using a photochemical procedure at moderately elevated temperature.

1. Selected reviews and articles: (a) Grée, R. Synthesis 1989, 341–355; (b) Fatiadi, A. J. J. Res. Natl. Inst. Stand. Technol. 1991, 96, 1; (c) Knölker, H.-J. Synlett 1992, 371–387; (d) Knölker, H.-J. Chem. Rev. 2000, 100, 2941–2961; (e) Pearson, A. J. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; Jai Press: Greenwich, 1989; Vol. 1, pp 1–49; (f) Pearson, A. J. Iron Compounds in Organic Synthesis. In Best Synthetic Methods; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Academic Press, 1994; (g) Roush, W. R.; Wada, C. K. Tetrahedron Lett. 1994, 35, 7347–7350; (h) Cleator, E.; Harter, J.; Hollowood, C. J.; Ley, S. V. Org. Biomol. Chem. 2003, 1, 3263–3264. and references cited therein; (i) Lee, D. W.; Pandey, R. K.; Lindeman, S.; Donaldson, W. A. Org. Biomol. Chem. 2011, 9, 7742–7747. and references cited therein; (j) El-Mansy, M. F.; Sar, A.; Lindeman, S.; Donaldson, W. A. Chem. Eur. J. 2013, 19, 2330–2366. and references cited therein. 2. (a) Pearson, A. J.; Zettler, M.; Pinkerton, A. A. J. Chem. Soc., Chem. Commun. 1987, 264–266; (b) Pearson, A. J.; Zettler, M. W. J. Am. Chem. Soc. 1989, 111, 3908–3918. 3. Pearson, A. J.; Alimardanov, A.; Pinkerton, A. A.; Parrish, D. A. J. Org. Chem. 1998, 63, 6610–6618. 4. Pearson, A. J.; Wang, X.; Dorange, I. B. Org. Lett. 2004, 6, 2535–2538. 5. (a) Pearson, A. J.; Wang, X. J. Am. Chem. Soc. 2003, 125, 638–639; (b) Pearson, A. J.; Wang, X. Tetrahedron Lett. 2005, 46, 3123–3126; (c) Pearson, A. J.; Sun, H.; Wang, X. J. Org. Chem. 2007, 72, 2547–2557. 6. We have previously described the use of vinyl ethers in single ene-type cyclizations related to that shown in Eq. 1: Pearson, A. J.; Zhang, S.; Sun, H. J. Org. Chem. 2012, 77, 8835–8839. 7. Birch, A. J.; Williamson, D. H. J. Chem. Soc., Perkin Trans. 1 1973, 1892–1900. 8. Pearson, A. J.; Dorange, I. B. J. Org. Chem. 2001, 66, 3140–3145. 9. Wada, A.; Hiraishi, S.; Takamura, N.; Date, T.; Aoe, K.; Ito, M. J. Org. Chem. 1997, 62, 4343–4348. 10. Pearson, A. J.; Wang, X. Tetrahedron Lett. 2005, 46, 4809–4811.

Acknowledgments We are grateful to the National Science Foundation (CHE-0743234) and the Department of Chemistry, Case Western Reserve University, for financial support. Supplementary data Supplementary data (experimental procedures and characterization data for all new compounds) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.tetlet.2014.11.129.